Pharmacology of

antiepileptic
 Epilepsy
Approximately 10% of the population will have at least one seizure in
their lifetime.
Epilepsy is a heterogeneous symptom complex—a chronic disorder
characterized by recurrent seizures.
Seizures are finite episodes of brain dysfunction resulting from
abnormal discharge of cerebral neurons.
The causes of seizures are many and include the full range of
neurologic diseases—from infection to neoplasm and head injury.
 Classification Of Seizures
Seizures have been classified into two broad groups: focal( partial) and
generalized.
1. Focal: Focal seizures involve only a portion of the brain, typically part
of one lobe of one hemisphere. The symptoms of each seizure type
depend on the site of neuronal discharge and on the extent to which
the electrical activity spreads to other neurons in the brain. Focal
seizures may progress to become generalized tonic–clonic seizures.
A. Focal aware seizure (Simple partial): These seizures are caused by a
group of hyperactive neurons exhibiting abnormal electrical activity
and are confined to a single locus in the brain. The electrical discharge
does not spread, and the patient does not lose consciousness or
awareness. The patient often exhibits abnormal activity of a single
limb or muscle group that is controlled by the region of the brain
experiencing the disturbance.
B. Focal impaired awareness seizure (Complex partial): These seizures
exhibit complex sensory hallucinations and mental distortion. Motor
dysfunction may involve chewing movements, diarrhea, and/or
 Classification Of Seizures
2. Generalized: Generalized seizures may begin locally and then
progress to include abnormal electrical discharges throughout both
hemispheres of the brain.
A. Tonic–clonic: These seizures result in loss of consciousness, followed
by tonic (continuous contraction) and clonic (rapid contraction and
relaxation) phases.
B. Absence: These seizures involve a brief, abrupt, and self limiting loss
of consciousness. The onset generally occurs in patients at 3 to 5 years
of age and lasts until puberty or beyond. The patient stares and
exhibits rapid eye-blinking, which lasts for 3 to 5 seconds.
C. Myoclonic: These seizures consist of short episodes of muscle
contractions that may recur for several minutes.
 Classification Of Seizures
D. Clonic: These seizures consist of short episodes of
muscle contractions that may closely resemble myoclonic
seizures. Consciousness is more impaired with clonic
seizures as compared to myoclonic.
E. Tonic: These seizures involve increased tone in the
extension muscles and are generally less than 60 seconds
long.
F. Atonic: These seizures are also known as drop attacks and
are characterized by a sudden loss of muscle tone.
 Drugs
Drugs Used In Partial Seizures & Generalized Tonic-Clonic
Seizures
The classic major drugs for partial and generalized tonic-
clonic seizures are phenytoin (and congeners),
carbamazepine, valproate, and the barbiturates. While the
newer drugs involve eslicarbazepine, lamotrigine,
levetiracetam, gabapentin, oxcarbazepine, pregabalin,
retigabine, topiramate, vigabatrin, lacosamide, and
zonisamide
 MECHANISMS OF ACTION
The general effect of antiseizure drugs is to suppress repetitive
action potentials in epileptic foci in the brain. Many different
mechanisms are involved in achieving this effect.
1. Sodium channel blockade
2. Enhancement of inhibitory GABA synapses
3. Inhibition of excitatory glutamate activity. In some cases, several
mechanisms may contribute to the antiseizure activity of an
individual drug.
 MECHANISMS OF ACTION
A. Sodium Channel Blockade
At therapeutic concentrations, phenytoin, carbamazepine,
lacosamide, lamotrigine, and zonisamide block voltage-gated
sodium channels in neuronal membranes. Topiramate may also
act, in part, by this mechanism. This action is rate-dependent (ie,
block increases with increased frequency of neuronal discharge)
and results in prolongation of the inactivated state of the Na+
channel and the refractory period of the neuron. Phenobarbital
and valproic acid may exert similar effects at high doses.
 MECHANISMS OF ACTION
B. GABA-Related Targets
Benzodiazepines interact with specific receptors on the GABAA receptor–
chloride ion channel macromolecular complex and facilitate the inhibitory
effects of GABA. Phenobarbital and other barbiturates also
enhance the inhibitory actions of GABA but interact with a
different receptor site on chloride ion channels
GABA aminotransaminase (GABA-T) is an important enzyme in
the termination of action of GABA. The enzyme is irreversibly
inactivated by vigabatrin at therapeutic plasma levels and can
also be inhibited by valproic acid at very high concentrations.
Tiagabine inhibits a GABA transporter (GAT-1) in neurons and
glia, prolonging the action of the neurotransmitter. Gabapentin
and pregabalin modify the synaptic or nonsynaptic release of
GABA. Other drugs that may facilitate the inhibitory actions of
GABA include felbamate, topiramate, and valproic acid.
 MECHANISMS OF ACTION
C. Calcium Channel Blockade
Ethosuximide inhibits low-threshold (T type) Ca
currents, especially in thalamic neurons that act as
pacemakers to generate rhythmic cortical discharge. A
similar action is reported for valproic acid, as well as
for both gabapentin and pregabalin, and it may be
the primary action of the latter drugs, especially at
glutamate nerve terminals.
 MECHANISMS OF ACTION
D. Glutamate Synapses and Other Mechanisms
Levetiracetam binds the SV2A protein on glutamate-
containing transmitter vesicles and reduces glutamate
release. In addition to its action on calcium channels,
valproic acid causes neuronal membrane
hyperpolarization, possibly by enhancing K+ channel
permeability. Retigabine also enhances K+ channel
activity and inhibits depolarization of glutamate
terminals. Perampanel is a noncompetitive antagonist
at glutamate AMPA receptors and may be particularly
effective in preventing the spread of abnormal
excitation in susceptible neurons. Felbamate blocks
glutamate NMDA receptors. Although phenobarbital
acts on both sodium channels and GABA-chloride
 Phenytoin
C. Pharmacokinetics
Phenytoin : is the oldest nonsedative antiseizure drug, introduced in 1938
 Absorption of phenytoin is highly dependent on the formulation of the
dosage form. Particle size and pharmaceutical additives affect both the
rate and the extent of absorption.
 Absorption of phenytoin sodium from the gastrointestinal tract is
nearly complete in most patients, although the time to peak may range
from 3 to 12 hours.
Absorption after intramuscular injection is unpredictable. In contrast,
fosphenytoin, a more soluble phosphate prodrug of phenytoin, is well
absorbed after intramuscular administration.
Phenytoin is highly bound to plasma proteins.
Phenytoin is metabolized to inactive metabolites that are excreted in
the urine.
 Phenytoin
C. Pharmacokinetics
The elimination of phenytoin is dose-dependent. At very low blood
levels, phenytoin metabolism follows first-order kinetics. However, as
blood levels rise within the therapeutic range, the maximum capacity
of the liver to metabolize phenytoin is approached. Further increases
in dosage, though relatively small, may produce very large changes in
phenytoin concentrations
D. Toxicity
1. Dose-related adverse effects caused by phenytoin are often similar to
those caused by other antiseizure drugs in this group,
2. Nystagmus occurs early
3. Diplopia and ataxia are the most common dose-related adverse effects
requiring dosage adjustment
 Phenytoin
D. Toxicity
4. sedation usually occurs only at considerably higher levels.
5. Gingival hyperplasia and hirsutism occur to some degree in most
patients;
6. Long-term use is associated in some patients with coarsening of facial
features and with mild peripheral
7. neuropathy, usually manifested by diminished deep tendon reflexes in
the lower extremities.
8. Long-term use may also result in abnormalities of vitamin D
metabolism, leading to osteomalacia.
9. Low folate levels and megaloblastic anemia have been reported,
 MEPHENYTOIN, & ETHOTOIN
mephenytoin and ethotoin, like phenytoin, appear to be most effective
against generalized tonic-clonic seizures and partial seizures.
Ethotoin may be recommended for patients who are hypersensitive to
phenytoin, but larger doses are required.
The adverse effects and toxicity are generally less severe than those
associated with phenytoin, but the drug appears to be less effective.
Both ethotoin and mephenytoin share with phenytoin the property of
saturable metabolism within the therapeutic dosage range. Careful
monitoring of the patient during dosage alterations with either drug is
essential.
.
 CARBAMAZEPINE
Pharmacokinetics
 Carbamazepine almost completely absorbe after oral administration
 Peak levels are usually achieved 6–8 hours after administration.
 Slowing absorption by giving the drug after meals helps the patient
tolerate larger total daily doses.
 Carbamazepine has a notable ability to induce microsomal enzymes.
 Typically, the half-life of 36 hours observed in subjects after an initial
single dose decreases to as little as 8–12 hours in subjects receiving
continuous therapy. Considerable dosage adjustments are thus to be
expected during the first weeks of therapy.
 Carbamazepine also alters the clearance of other drugs eg, primidone,
phenytoin, ethosuximide, valproic acid, and clonazepam
 Carbamazepine is completely metabolized in humans to several
derivatives.
 CARBAMAZEPINE
Toxicity
1. The most common dose-related adverse effects of carbamazepine are
diplopia and ataxia.
2. Other dose-related complaints include mild gastrointestinal upsets,
unsteadiness, and, at much higher doses, drowsiness.
3. Hyponatremia and water intoxication have occasionally occurred and
may be dose related.
4. idiosyncratic blood dyscrasias, including fatal cases of aplastic
anemia and agranulocytosis.
5. The most common idiosyncratic reaction is an erythematous skin
rash
OXCARBAZEPINE, ESLICARBAZINE (ESL)
Clinically, the drugs are like carbamazepine in their spectrum and
mechanism of of action. Oxcarbazepine may have an improved
toxicity profile than carbamazepine but with less potency
Eslicarbazepine acetate is a prodrug that has been approved as adjunctive
therapy in adults with partial-onset seizures, with or without
secondary generalization.
PHENOBARBITAL and PRIMIDONE
Phenobarbital is useful in the treatment of partial seizures and
generalized tonic-clonic seizures, There is little evidence for its
effectiveness in generalized seizures such as absence, atonic attacks,
and infantile spasms. primidone was metabolized to phenobarbital and
phenylethylmalonamide (PEMA). All three compounds are active
anticonvulsants
FELBAMATE
Although it is effective in some patients with partial seizures,
the drug causes aplastic anemia and severe hepatitis at
unexpectedly high rates and has been relegated to the status
of a third-line drug for refractory cases.
Felbamate has a half-life of 20 hours metabolized by
hydroxylation and conjugation
A significant percentage of the drug is excreted unchanged in
the urine. When added to treatment with other antiseizure
drugs, felbamate increases plasma phenytoin and valproic
acid levels but decreases levels of carbamazepine
GABAPENTIN & PREGABALIN
Gabapentin is an amino acid, an analog of GABA, that is effective
against partial seizures. Pregabalin is another GABA analog, closely
related to gabapentin, and has been approved for both antiseizure
activity and for its analgesic properties
LACOSAMIDE
Lacosamide is an amino acid-related compound that has been studied in
both pain syndromes and partial seizures.
Lacosamide is approved as adjunctive therapy in the treatment of partial-
onset seizures with or without secondary generalization in patients
with epilepsy who are age 16–17 years and older.
Adverse effects were dizziness, headache, nausea, and diplopia.
LAMOTRIGINE
Clinical Uses
It is effective as monotherapy for partial seizures, and lamotrigine is now
widely prescribed for this indication.
The drug is also active against absence and myoclonic seizures in
children and is approved for seizure control in the Lennox-Gastaut
syndrome. Lamotrigine is also effective for bipolar disorder.
Adverse effects
Dizziness, headache, diplopia, nausea, somnolence, and skin rash. The
rash is considered a typical hypersensitivity reaction.
LEVETIRACETAM.
 Levetiracetam is marketed for the adjunctive treatment of
partial seizures in adults and children for primary
generalized tonic-clonic seizures and for the myoclonic
seizures of juvenile myoclonic epilepsy.
 Oral absorption of levetiracetam is rapid and nearly
complete, with peak plasma concentrations in 1.3 hours.
Food slows the rate of absorption but does not affect the
amount absorbed
 Adverse effects include somnolence, asthenia, ataxia,
infection (cold) and dizziness.
RETIGABINE (EZOGABINE)
 Retigabine is approved for the adjunctive treatment of
partial-onset seizures in adults.
 Absorption is not affected by food and kinetics are linear;
drug interactions are minimal.
 adverse effects are dose-related and include dizziness,
somnolence, blurred vision, confusion, and dysarthria.
Bladder dysfunction, mostly mild and related to the drug’s
mechanism of action, was observed in 8-9% of patients
TIAGABINE
 Tiagabine is indicated for the adjunctive treatment of
partial seizures and is
 Minor adverse events are dose related and include
nervousness, dizziness, tremor, difficulty in concentrating,
and depression. Excessive confusion, somnolence, or
ataxia may require discontinuation.
TOPIRAMATE
Clinical Uses and adverse effect
topiramate as monotherapy demonstrated efficacy against partial and
generalized tonic-clonic seizures.
The drug is also approved for the Lennox-Gastaut syndrome and may be
effective in infantile spasms and even absence seizures.
Topiramate is also approved for the treatment of migraine headaches.
dose-related adverse effects occur most frequently in the first 4 weeks
and include somnolence, fatigue, dizziness, cognitive slowing,
paresthesias, nervousness, and confusion.
VIGABATRIN
 Vigabatrin is useful in the treatment of partial seizures and infantile
spasms. The half-life is approximately 6–8 hours, but considerable
evidence suggests that the pharmacodynamic activity of the drug is
more prolonged and not well correlated with the plasma half-life.
 Typical toxicities include drowsiness, dizziness, and weight gain.
 long-term therapy with vigabatrin has been associated with
development of peripheral visual field defects in 30–50% of patients.
ZONISAMIDE
 Itis effective against partial and generalized tonic-clonic seizures and
may also be useful against infantile spasms and certain myoclonias.
 Adverse effects include drowsiness, cognitive impairment, and
potentially serious skin rashes
DRUGS USED IN GENERALIZED SEIZURES
ETHOSUXIMIDE
 Ethosuximide is particularly effective against absence
seizures
 Data continue to show that ethosuximide and valproate are
the drugs of choice for absence seizures and are more
effective than lamotrigine.
 The most common dose-related adverse effect of
ethosuximide is gastric distress, including pain, nausea,
and vomiting.
 Other dose-related adverse effects are transient lethargy or
fatigue and, much less commonly, headache, dizziness,
hiccup, and euphoria.
VALPROIC ACID & SODIUM VALPROATE and divalproex
 Like phenytoin and carbamazepine, valproate blocks sustained high-
frequency repetitive firing of neurons in culture at therapeutically
relevant concentrations.
 Blockade of NMDA receptor-mediated excitation may also be
important.
 Valproate is very effective against absence seizures and is often
preferred to ethosuximide when the patient has concomitant
generalized tonic-clonic attacks.
 Valproate is unique in its ability to control certain types of myoclonic
seizures; in some cases the effect is very dramatic.
 Divalproex is a combination of valproic acid and sodium valproate
that converted to valproate ion in the GIT it introduce in order to
improve GIT tolerance to valproic acid
VALPROIC ACID & SODIUM VALPROATE.
 The drug is effective in tonic-clonic seizures, especially those that are
primarily generalized.
 Other uses of valproate include management of bipolar disorder and
migraine prophylaxis.
 Food may delay absorption, and decreased toxicity may result if the
drug is given after meals.
 Valproic acid is 90% bound to plasma proteins
 The most common dose-related adverse effects of valproate are
nausea, vomiting, and other gastrointestinal complaints such as
abdominal pain and heartburn
 Other Drugs Used In Management Of Epilepsy Benzodiazepines
Seven benzodiazepines play prominent roles in the therapy of epilepsy
1. Diazepam given intravenously or rectally is highly effective in
generalized tonic-clonic status epilepticus
2. Lorazepam: it is more effective and longer acting than diazepam .
3. Clonazepam is a long-acting drug effective in some cases of
myoclonic seizures, absence seizures and infantile spasms.
4. Nitrazepam is used for infantile spasms and myoclonic seizures. It is
less potent than clonazepam
5. Clorazepate dipotassium is approved as an adjunct to treatment of
complex partial seizures in adults.
6. Midazolam is preferred in the out-of-hospital treatment of status
epilepticus because the delay required to achieve intravenous access
may be avoided.
7. Clobazam is widely used for the treatment of focal seizures and
seizures associated with Lennox-Gastaut syndrome in patients 2
years of age or older.
 OTHER DRUGS USED IN MANAGEMENT OF
EPILEPSY
ACETAZOLAMIDE
 Acetazolamide is a diuretic whose main action is the
inhibition of carbonic anhydrase
 Mild acidosis in the brain may be the mechanism by which
the drug exerts its antiseizure activity
 Acetazolamide has been used for all types of seizures but
is severely limited by the rapid development of tolerance,
with return of seizures usually within a few weeks.
 The drug may have a special role in epileptic women who
experience seizure exacerbations at the time of menses;
seizure control may be improved and tolerance may not
develop because the drug is not administered continuously.
 Clinical Uses
Diagnosis of a specific seizure type is important for
prescribing the most appropriate antiseizure drug (or
combination of drugs). Drug choice is usually made on the
basis of
1. Established efficacy in the specific seizure state that has
been diagnosed
2. The prior responsiveness of the patient
3. The anticipated toxicity of the drug
4. Possible drug interactions.
Treatment may involve combinations of drugs, following the
principle of adding known effective agents if the preceding
drugs are not sufficient.
 2. Other Clinical Uses
1. Several antiseizure drugs are effective in the management of bipolar
affective disorders, especially valproic acid, which is now often used
as a first-line drug in the treatment of mania. Carbamazepine and
lamotrigine have also been used successfully in bipolar disorder.
2. Carbamazepine is the drug of choice for trigeminal neuralgia, and its
congener oxcarbazepine may provide similar analgesia with fewer
adverse effects.
3. Gabapentin has efficacy in pain of neuropathic origin, including
postherpetic neuralgia, and, like, may have some value in migraine.
4. Topiramate and phenytoin are also used in the treatment of migraine.
5. Pregabalin is also approved for use in neuropathic pain, including
painful diabetic peripheral neuropathy and postherpetic neuralgia. It
is the first drug in the USA approved for fibromyalgia.It is also
approved for generalized anxiety disorder
.